Contribution Of Individual Components Research Articles

Genome editing of peptide loading reveals risks of immunotherapeutic targeting of TAP1 independent peptides

Current immunotherapeutic strategies for cancer aim to target HLA class I (HLA-I) presented neo-epitopes. A subgroup of neo-epitopes has been proposed to be presented only in the absence of the TAP transporter. We here identified a novel TAP-independent antigen that was surprisingly effectively presented by TAP-sufficient cells. We engineered a library of HLA-I pathway CRISPR/Cas9-mediated knockout cells on a single genetic background allowing for an optimal comparison of individual component contributions to antigen presentation. Sequence-verified knockouts for HLA-I (-A, -B and -C), B2M, Calnexin, α-Glucosidase II, Calreticulin, ERAP1, TAP1, Tapasin and ERp57 were created. The HLA-I surface expression of these cells depended on both the targeted gene and the detected HLA-I allele, as expected. To investigate the presentation of single antigens, we targeted the knockout library with a panel of peptide-specific T cell clones. Surprisingly, T cells specific for a peptide derived from the endogenously expressed SSR1 protein recognized TAP1-deficient cells at a similar efficiency as wild type cells. These T cells were derived from a patient during graft-versus-host-disease, suggesting that they contributed to the destruction of healthy TAP-sufficient cells. Further experiments demonstrated the functional presentation of the SSR1 antigen by various healthy cells, underscoring that TAP-independent antigens can contribute to unwanted T cell reactivity. In conclusion, we generated and validated a novel cellular toolset that allows comparative research in the HLA-I antigen processing and presentation pathway. Using this toolset we found a TAP-independent peptide that is functionally presented on healthy cells. Our data underscore potential pitfalls of targeting TAP-independent antigens as immunotherapeutic approach

Hazard Profiling of Commercially Relevant Quantum Dot Components Revealed Synergistic Interactions between Heavy Metals and Polymers

Commercially used quantum dots (QDs) exemplify complex nanomaterials with multiple components, though little is known about the type of interactions between these components in determining the overall toxicity of this material. We synthesized and characterized a functional QD (CdSe/ZnS_P&E) that was identical in structure and composition to a patented and commercially applied QD and the combinations of its components (CdSe, CdSe/ZnS, ZnS, CdSe_P&E, ZnS_P&E, and P&E). Cells exposed to incremental concentrations of these materials were investigated for cell viability and cellular perturbations, contributing to a final common pathway of cell death using high-content screening assays in model human intestinal epithelial cells (HIEC-6). The concentrations that resulted in a loss of 20% cell viability (EC20 values) for each tested component were used for estimating the combination index (CI) to evaluate synergistic or antagonistic effects between the components. Complete QD (core/shell-polymer) showed the highest toxic potential due to synergistic interactions between core and surface functional groups. The cationic polymer coating enhanced cellular uptake of the QD, ensuing lysosome acidification and release of heavy metal ions to the intracellular milieu, and caused oxidative stress and cytotoxicity. Overall, this study advances our understanding of the collective contribution of individual components of a functional QD toward its toxic potential and emphasizes the need to study multilayered nanomaterials in their entirety for hazard characterization.

Lower All-Cause Mortality for Coronary Heart or Stroke Patients Who Adhere Better to Mediterranean Diet-An NHANES Analysis.

Consuming a Mediterranean-style diet (MED) is helpful for primary prevention of atherosclerotic cardiovascular disease (ASCVD). However, few studies have compared mortality in ASCVD subjects with different degrees of adherence to the MED diet or have evaluated the contributions of individual diet components. We analyzed National Health and Nutrition Examination Survey (NHANES) participants with a history of coronary heart disease (CHD) or stroke (N = 2052) in a period from 1999 to 2010. Their individual vital status was linked to the National Death Index till the end of 2011. The level of adherence to the MED diet was quantified using a 9-point evaluation score (aMED score). Cox regression models were used to compare the different levels of adherence to the MED diet, and contributions of individual components of the MED diet on cardiovascular, cancer, and all-cause mortality. Among the 2052 subjects with CHD or stroke, 29.0% (596 of 2052) died after a median follow-up of 5.6 years. In Cox regression analysis, higher absolute aMED score (HR 0.798, p = 0.0079) or above median aMED score (score 4–9) (HR 0.646, p = 0.0013) was negatively associated with all-cause mortality. Among various components of the MED diet, intake of more whole grains or nuts was significantly associated with a lower all-cause mortality. In contrast, a higher aMED score was not associated with less cardiovascular mortality. In a secondary analysis that excluded deaths within 2 years of the NHANES study entry, the above median aMED score (score 4–9) was negatively associated with both all-cause and cardiovascular mortality. In conclusion, subjects with a history of CHD or stroke adhering better to the MED diet in the NHANES study had a lower all-cause mortality during follow-ups. Consuming more whole grains or nuts had a lower all-cause mortality. The protective effect of adherence to the MED diet on decreasing cardiovascular mortality was seen only after excluding those who died within first two years of the NHANES study entry.

Impact of program characteristics on weight loss in adult behavioral weightmanagement interventions: systematic review and component network meta-analysis.

ObjectiveBehavioral weight management programs (BWMPs) for adults lead to greater weight loss at 12 months than minimal‐intervention control treatments. However, there is considerable heterogeneity in the content of BWMPs and outcomes of treatment. This study assessed the contribution of individual components of BWMPs, using Bayesian component network meta‐analysis.MethodsRandomized controlled trials of BWMPs in adults were identified (latest search: December 2019) and arms coded for presence or absence of 29 intervention components grouped by type, content, provider, mode of delivery, and intensity.ResultsA total of 169 studies (41 judged at high risk of bias) were included in the main analysis. Six components had effect estimates indicating clinically significant benefit and credible intervals (CrIs) excluding no difference: change in diet (mean difference [MD] = −1.84 kg, 95% CrI: −2.91 to −0.80); offering partial (MD = −2.12 kg, 95% CrI: −3.39 to −0.89) or total meal replacements (MD = −2.63 kg, 95% CrI: −4.58 to −0.73); delivery by a psychologist/counselor (MD = −1.45 kg, 95% CrI: −2.81 to −0.06) or dietitian (MD = −1.31 kg, 95% CrI: −2.40 to −0.24); and home setting (MD = −1.05 kg, 95% CrI: −2.02 to −0.09).ConclusionsFuture program development should consider including these components; other approaches continue to warrant evaluation of effectiveness.

Synergistic Mechanism of Platinum-GaOx Catalysts for Propane Dehydrogenation.

The synergy between metals and metal oxides can effectively improve the heterogeneous catalytic process. This paper describes the intrinsic effect of Pt modification over GaOx (Pt-GaOx ) on propane dehydrogenation. The presence of Pt promotes H2 dissociation and surface coverage of hydrogen species, which is beneficial for the activation of C-H in propane. With excessive Pt, Gaδ+ can be further reduced to form Pt-Ga alloy with less surface hydrogen species. Consequently, the relative propylene formation rate between Pt-GaOx and the summed contribution of individual Pt and GaOx increases linearly with the content of hydrogen species. Optimally, the relative propylene formation rate of Pt-GaOx with 0.03 wt % Pt exceeds 25 % of the summed contribution of individual components.

Synergistic Mechanism of Platinum‐GaOx Catalysts for Propane Dehydrogenation

AbstractThe synergy between metals and metal oxides can effectively improve the heterogeneous catalytic process. This paper describes the intrinsic effect of Pt modification over GaOx (Pt−GaOx) on propane dehydrogenation. The presence of Pt promotes H2 dissociation and surface coverage of hydrogen species, which is beneficial for the activation of C−H in propane. With excessive Pt, Gaδ+ can be further reduced to form Pt−Ga alloy with less surface hydrogen species. Consequently, the relative propylene formation rate between Pt−GaOx and the summed contribution of individual Pt and GaOx increases linearly with the content of hydrogen species. Optimally, the relative propylene formation rate of Pt−GaOx with 0.03 wt % Pt exceeds 25 % of the summed contribution of individual components.

Ternary Nanohybrid of Ni3S2/CoMoS4/MnO2 on Nickel Foam for Aqueous and Solid-State High-Performance Supercapacitors.

To overcome the issues related to supercapacitor (SC) electrodes, such as high cost, low specific capacitance (Cs), low energy density (ED), requirements for expensive binder, etc., binderless electrodes are highly desirable. Here, a new ternary nanohybrid is presented as a binder-free SC electrode based on Ni3S2, CoMoS4, and MnO2. A facile two-step hydrothermal route, followed by a short thermal annealing process, is developed to grow amorphous polyhedral structured CoMoS4 and further wrap MnO2 nanowires on Ni foam. This rationally designed binder-free electrode exhibited the highest Cs of 2021 F g−1 (specific capacity of 883.8 C g−1 or 245.5 mAh g−1) at a current density of 1 A g−1 in 1 M KOH electrolyte with a highly porous surface morphology. This electrode material exhibited excellent cycling stability (90% capacitance retention after 4000 cycles) due to the synergistic contribution of individual components and advanced surface properties. Furthermore, an aqueous binder-free asymmetric SC based on this ternary composite exhibited an ED of 20.7 Wh kg−1, whereas a solid-state asymmetric SC achieved an ED of 13.8 Wh kg−1. This nanohybrid can be considered a promising binder-free electrode for both aqueous and solid-state asymmetric SCs with these remarkable electrochemical properties.

Experimental Analysis and Modeling of Closed-Loop Redox Flow Desalination

Redox flow desalination (RFD) is an emerging electrochemical process utilizing a redox couple for salt separation, which enables continuous and energy-efficient brackish water desalination. Several redox couples have been used to desalinate water along with energy production (from sustainable sources such as sunlight) and storage. However, an in-depth analysis of the redox reactions and ion transport that occur simultaneously in different components of an RFD electrochemical cell is still lacking. We carried out a series of experiments, with different cell configurations, to elucidate the contribution of individual components to the cell voltage. A closed-loop RFD mediated by ferri-/ferrocyanide as a model redox couple was designed for this analysis. The cell voltage gradually increased as the diluate concentration decreased from 3 to 0.5 g l−1, attributed to the solution resistance, membrane resistance, Donnan potential, and overpotential of the redox reaction. We experimentally measured voltage drops due to each component, the sum of which was in good agreement with the time-variant cell voltage. A phenomenological model was used to fit the experimental concentration and voltage data, and a good fit was obtained. The combined experimental and modeling analysis reported herein is expected to guide a rational design and operation of RFD processes.

European LeukemiaNet Response Predicts Disease Progression but Not Thrombosis in Polycythemia Vera.

European LeukemiaNet Response Predicts Disease Progression but Not Thrombosis in Polycythemia Vera.

Lubrication properties of model dairy beverages: Effect of the characteristics of protein dispersions and emulsions

In this study we investigated the individual contribution of different ingredients to the lubrication properties of dairy-based model beverages containing whey protein (native or aggregated), micellar casein and emulsified oil in different combinations. In single-component systems, whey protein isolate (WPI) solutions showed the lowest friction coefficients of all protein samples. Whey protein aggregates (WPA, ∼247 nm, irregular morphology) led to higher friction coefficients than micellar casein isolate (MCI) with comparable size (∼207 nm, near spherical shape). When protein particles were combined, i.e. WPA and MCI, lubrication was not much affected. However, when WPI was added to either WPA or MCI, higher friction coefficients were observed compared to single-component systems. Emulsions (droplet size ∼ 440 nm) provided better lubrication than the protein samples. Oil droplets stabilized by soy lecithin (SL) were more efficient at reducing friction than those stabilized by WPI. The friction coefficient of SE strongly increased in the presence of WPI. In comparison, lubrication of WE was less affected by the addition of WPI. These results show that different proteins affect the lubrication properties of emulsions stabilized with different emulsifiers in a different way. Our research also indicates that multicomponent systems are complex, and that control over the lubrication properties requires a better understanding of the contribution of individual components.

Trauma-induced coagulopathy: Mechanisms and clinical management

Trauma-induced coagulopathy (TIC) is a form of coagulopathy unique to trauma patients and is associated with increased mortality. The complexity and incomplete understanding of TIC have resulted in controversies regarding optimum management. This review aims to summarise the pathophysiology of TIC and appraise established and emerging advances in the management of TIC. This narrative review is based on a literature search (MEDLINE database) completed in October 2020. Search terms used were "trauma induced coagulopathy", "coagulopathy of trauma", "trauma induced coagulopathy pathophysiology", "massive transfusion trauma induced coagulopathy", "viscoelastic assay trauma induced coagulopathy", "goal directed trauma induced coagulopathy and "fibrinogen trauma induced coagulopathy'. TIC is not a uniform phenotype but a spectrum ranging from thrombotic to bleeding phenotypes. Evidence for the management of TIC with tranexamic acid, massive transfusion protocols, viscoelastic haemostatic assays (VHAs), and coagulation factor and fibrinogen concentrates were evaluated. Although most trauma centres utilise fixed-ratio massive transfusion protocols, the "ideal" transfusion ratio of blood to blood products is still debated. While more centres are using VHAs to guide blood product replacement, there is no agreed VHA-based transfusion strategy. The use of VHA to quantify the functional contributions of individual components of coagulation may permit targeted treatment of TIC but remains controversial. A greater understanding of TIC, advances in point-of-care coagulation testing, and availability of coagulation factors and fibrinogen concentrates allows clinicians to employ a more goal-directed approach. Still, hospitals need to tailor their approaches according to available resources, provide training and establish local guidelines.

Disentangling polydisperse biomolecular systems by Chemometrics decomposition of SAS data.

The structural characterization of polydisperse systems consisting of multiple coexisting species or conformations is very challenging or impossible with classical approaches. As a consequence, the structural bases of relevant questions related to protein folding, transient partner recognition, conformational transitions or fibrillation remain poorly understood. Small-Angle Scattering (SAS) techniques structurally probe species present in solution in a population-weighted manner, enabling the inspection of polydisperse systems. However, decomposition of these data to derive the contribution of individual components is not straightforward and requires the acquisition of large SAS datasets and adapted mathematical tools. Here, we present a detailed procedure for the usage of the program COSMiCS for the decomposition of SAS datasets. COSMiCS adapts the popular MCR-ALS chemometrics routine to the specificities of scattering data. Through the use of multiple SAS representations, the appropriate scaling of the data and the possibility to simultaneously decompose multiple orthogonal datasets, COSMiCS efficiently disentangles mixtures and provides species-specific structural and thermodynamic/kinetic information of the process under investigation. Although exemplified for a transient biomolecular interaction, our chemometrics strategy can be applied to many other biological processes that can be straightforwardly probed in last generation SAS beamlines. Indeed, recent experimental setups, including microfluidics and stop-flow devices, coupled to fast-reading detectors can yield large concentration or time-dependent datasets that can be decomposed with COSMiCS. Importantly, as an open-source code, previously known features of the system of interest can be introduced as constraints in the optimization, producing robust solutions for biological systems of increasing complexity.

Meta-Ranker: Efficient Design of Combination Drug Products for Complex Diseases

Developing multi-targeting combination drug products for complex diseases is necessary to achieve appropriate efficacy benchmarks and translate into meaningful improvements for the patient. Meta-ranker is an algorithm to discover and design novel combinations to advance the leading investigational product candidate based on their effects on an array of phenotypes. Meta-ranker is leveraged during clinical development to elucidate the contribution of individual components to fulfill regulatory requirements for fixed combinations. Here, we detail the algorithm's specific steps, introduce the weight parameter, and highlight potential implications of endogenous metabolic modulators applied as combinations in a liver disease model.

Modeling of Air Flow Over a Generic Aircraft Carrier With and Without Island Structure

The study of external aerodynamics of an aircraft carrier is of utmost importance in ensuring the safety of aircraft and pilots during take-off and recovery. The velocity deficit in the forward direction and the downwash together combine to give a sinking effect to the aircraft, along its glideslope path and is known as the ‘burble’ in naval aviation parlance. This phenomenon is primarily responsible for the potential increase in pilot workload on approach to the aircraft carrier. There is little literature in the open domain regarding ways and means to alleviate the burble effect. Unlike in the case of the automobile industry, which has the generic ‘Ahmed body’ and for the frigates/destroyers, for which there is the Simplified Frigate Ship (SFS), on which experiments and validation through CFD could be carried out, by researchers from all over the world, there is no generic Aircraft Carrier model for carrying out experiments and validation of CFD codes. The aim of this study is to define the Generic Aircraft Carrier Model (GAC), as developed at IIT Delhi, and to carry out numerical studies on the GAC and a variant of GAC without the island, BGAC (Baseline GAC), to assess the contribution of the island to the burble behind an Aircraft Carrier. This study gives a quantitative estimation of the effect and contribution of individual components of an Aircraft Carrier (like flight deck, island, etc.) to the burble behind the carrier, and would give a Naval Ship Designer an understanding of the effect of the geometrical configuration of the flight deck and the island on generation of the burble behind the carrier, which could aid the designer in potentially reducing the pilot workload.

The epigenetic mechanisms regulating floral hub genes and their potential for manipulation.

Gene regulatory networks formed by transcription factors play essential roles in the regulation of gene expression during plant reproductive development. These networks integrate endogenous, phytohormonal, and environmental cues. Molecular genetic, biochemical, and chemical analyses performed mainly in Arabidopsis have identified network hub genes and revealed the contributions of individual components to these networks. Here, I outline current understanding of key epigenetic regulatory circuits identified by research on plant reproduction, and highlight significant recent examples of genetic engineering and chemical applications to modulate the epigenetic regulation of gene expression. Furthermore, I discuss future prospects for applying basic plant science to engineer useful floral traits in a predictable manner as well as the potential side effects.

Electronic Medical Record Entity Recognition via Machine Reading Comprehension and Biaffine

The entity recognition of Chinese electronic medical record is of great significance to medical decision-making. The main process of entity recognition is sequence tagging, which has problems such as nested entity and boundary prediction. In this paper, we proposed a NER method called Bert-MRC-Biaffine, which formulates the NER as an MRC task. The approach of the machine reading comprehension framework is to introduce prior knowledge, the query about entities. The biaffine mechanism scores pair start and end tokens in a sentence so that the model is able to predict named entities accurately. The proposed method outperforms from the electronic medical record dataset, called CCKS2017 data, and the TCM dataset. We also remove components to evaluate the contribution of individual components of our model. Experiments on two datasets demonstrate the effectiveness of our model.

Achieving a \u201cstep change\u201d in the tuberculosis epidemic through comprehensive community-wide intervention: a model-based analysis

BackgroundGlobal progress towards reducing tuberculosis (TB) incidence and mortality has consistently lagged behind the World Health Organization targets leading to a perception that large reductions in TB burden cannot be achieved. However, several recent and historical trials suggest that intervention efforts that are comprehensive and intensive can have a substantial epidemiological impact. We aimed to quantify the potential epidemiological impact of an intensive but realistic, community-wide campaign utilizing existing tools and designed to achieve a “step change” in the TB burden.MethodsWe developed a compartmental model that resembled TB transmission and epidemiology of a mid-sized city in India, the country with the greatest absolute TB burden worldwide. We modeled the impact of a one-time, community-wide screening campaign, with treatment for TB disease and preventive therapy for latent TB infection (LTBI). This one-time intervention was followed by the strengthening of the tuberculosis-related health system, potentially facilitated by leveraging the one-time campaign. We estimated the tuberculosis cases and deaths that could be averted over 10 years using this comprehensive approach and assessed the contributions of individual components of the intervention.ResultsA campaign that successfully screened 70% of the adult population for active and latent tuberculosis and subsequently reduced diagnostic and treatment delays and unsuccessful treatment outcomes by 50% was projected to avert 7800 (95% range 5450–10,200) cases and 1710 (1290–2180) tuberculosis-related deaths per 1 million population over 10 years. Of the total averted deaths, 33.5% (28.2–38.3) were attributable to the inclusion of preventive therapy and 52.9% (48.4–56.9) to health system strengthening.ConclusionsA one-time, community-wide mass campaign, comprehensively designed to detect, treat, and prevent tuberculosis with currently existing tools can have a meaningful and long-lasting epidemiological impact. Successful treatment of LTBI is critical to achieving this result. Health system strengthening is essential to any effort to transform the TB response.

The Bacillus subtilis Minimal Genome Compendium.

To better understand cellular life, it is essential to decipher the contribution of individual components and their interactions. Minimal genomes are an important tool to investigate these interactions. Here, we provide a database of 105 fully annotated genomes of a series of strains with sequential deletion steps of the industrially relevant model bacterium Bacillus subtilis starting with the laboratory wild type strain B. subtilis 168 and ending with B. subtilis PG38, which lacks approximately 40% of the original genome. The annotation is supported by sequencing of key intermediate strains as well as integration of literature knowledge for the annotation of the deletion scars and their potential effects. The strain compendium presented here represents a comprehensive genome library of the entire MiniBacillus project. This resource will facilitate the more effective application of the different strains in basic science as well as in biotechnology.

Fostering Holistic Development with a Designed Multisport Intervention in Physical Education: A Class-Randomized Cross-Over Trial.

Physical education (PE) is acknowledged as a relevant context for holistic child and youth development promotion. However, interventional research mostly builds on individual theories focused on specific outcome domains. This study presents a multisport enriched PE intervention that capitalizes on the intersection of different theory-based approaches to motor, cognitive and socio-emotional skills development promotion. With a cross-over design, 181 fifth graders, coming from a past class-randomized trial of enriched or traditional PE in their 1st–3rd grade, were stratified (based on their previous PE experience) and class-randomized to multisport enriched PE or control group. They completed pre-post assessments in motor and sport skills, cool (inhibition, working memory) and hot (decision making) executive functions, prosocial (empathy, cooperation) and antisocial (quick-temperedness, disruptiveness) behaviors. Children in the enriched PE group showed advantages in motor and prosocial skills after the intervention, which were linked by a mediation path, and an interactive effect of past and actual PE experience on decision making but no differential effects on other variables. The results suggest that a PE intervention designed with an integrative theory base, although not allowing disentangling the contribution of individual components to its efficacy, may help pursue benefits in motor and non-motor domains relevant to whole-child development.

Carbon price dynamics in ambitious climate mitigation scenarios: an analysis based on the IAMC 1.5 °C scenario explorer

We analyse global carbon price trajectories from integrated assessment studies of 2 °C and below-compatible emission pathways based on a new scenario ensemble that has been made publicly available together with other relevant data sets in the IAMC 1.5 °C Scenario Explorer. We complement and extent the findings of the initial study on carbon price variations in integrated assessment models of (Guivarch and Rogelji 2017 Carbon price variations in 2 °C scenarios explored, Carbon Pricing Leadership Coalition) by providing a broader and more robust empirical assessment based on a comprehensive statistical analysis. We discuss the prospects and challenges of in‐depth bivariate econometric analyses of key impact factors in data sets from integrated assessment models. We show that the amount of meta‐information reported for individual models differs significantly across all variables where a large part of all recorded scenario explorer variables can be attributed to only a small number of applied models. We analyse the trend patterns emerging from the analysed global carbon price trajectories based on a statistical trend identification procedure. About half of the analysed carbon price projections seem to be best characterised by long run exponential growth patterns in carbon prices. Moreover, we break down the explanatory contribution of individual components on global carbon prices by the Kaya identity, i.e. global GDP, primary energy intensity and emission intensity. We show that the price of carbon is lower in baseline scenarios with faster economic growth per capita, low‐energy consumption patterns and high potentials for low carbon technologies compared to fossil fuels. In contrast to previous findings, the observed carbon price developments are impacted much more strongly by scenario‐specific than by model‐specific influences. Next to the diagnostic indicators for models, further indicators for the categorization of scenarios describing key context and policy parameterisations applied in individual model runs should be developed and included in descriptions of integrated assessment studies.